Method of preparing dithiol monocarboxylic acids and esters



United States Patent Claims. (Cl. 260 399) This invention relates to a process of preparing organic; 16 compounds. More particularly, it relates to a processiof; preparing dithiol aliphatic acids and esters from benzylthio substituted keto aliphatic acids and esters.

In the copending application of one of us, Serial Number 284,205, filed April 24, 1952, was described the prep- 20 aration of omega[3-(1,2-dithiolanyl)]aliphatic. acids, salts and esters thereof. These compounds are described as oxidation inhibitors and growth supporting factors for certain microorganisms including S. fecalis, Tetrahymena gelez'i and some corynebacterium species. The compound 6,8-dithioocta-noic acid (thioctic acid) described in the above application has been found by F. Rausfch (th Session of the German Association of Internal, 'ciii', April 1954) to be useful in the unconscious condition d6- s'cribed as Hepatic coma which can be completely s'nspended by the use of' thioctic acid. I The report further: states that alpha keto acids are oxidized by" thioctic acid and it is therefore possible to reduce the inereased pyrsra eernic acid level in the blood of man by" are use: of thioctic acid; Thi'octic acid therefore eife'rt'si a cfalta effect on metabolism. Thioctic acid and relate c pounds described in the application Herinbefo'r'e' referred to is' prepared'fr'oina' di'thiol aliphatic acid such as 6,8- dithioloctanoic acid. A commercial method for the. prep.- aration of. 6,8-dithioloctanoic acid is therefore highly de- 40 sirable.

We have now, found that dithi'olaliphatic acid esters" can be prepared in good yields of pure product frombenzylthio substituted k'eto aliphatic acid esters without; lSgl'aj-f tion of intermediates in a single step process. Hydrolysis of theseestersyield the desired acids. The new process of preparingthe dithi'ol aliphatic acids, we Believe; can be' illustrated by the following equations:

.' fireman-e1 aiida-sni'all amount of nrineralj acidadd the mixture heatedtu The alcoholcan their be distilled off S-CH R V l m- -onisoncmi(cm).ooon' (III) R I H: 'onis' HOHHIZHWEMGOGR R ns c zn'ortionwmjxcoon' S's as inwhich and R' are hydrogen; or a lower allryl radical,

i pound; 11 and therefore Compound I plus alpha-toluene thiol in the reaction is equivalent to Compound III in the general process.

The preparation of the benzylthioketoaliphatic acid esters used" as starting material in the process of the presentinvention is described andclaimed in the eopending applicationpof one of us, Serial Number 387,025, filed October 19;; 1953 These intermediates can'bejcpm pounds such as methyl 5-beniylthio-3-l etopentanoate,

me h ."ifi i q eeqate;.m h ljrb az t th io S-ketolieptanoate, methyl 8-benzylthio 6-ketooctano ate, methyl8-benZylthio 6eketononanoate} etc. In a simi-' Iar'm'anner other esters such as ethyl, propyl, butyl, amyl, etc of these compounds can also be used in the process of'tlfepreseiit'iiiveiitioii. I it In accordance with the equations above; the present compounds are preparedby placing the benzylthio ketoaliphatic acid ester in a hydrogenation bomb along with alpha-toluene thiol andhydrog'eni'ri tlie presence of a sulfactive catalyst, The sulfactive catalyst can be those (rs-e ediby'lCope et al;, Journal of organic Chemistry 19; 385 (1953). The reaction is' generally carried out at a temperature within the range of C. to 250 C. at ajpressi re'ars oo to 2500 p, s, i. for aperiod of from thirty m'iriutesto ten hours. The product obtained at the fi "iteie f e' a a li ia fli -b hz lt i a ph illustrated py (III) in the above equa' h ri ed i t ea wi ,s fi l a lfie paste' andhydrogen one benzylthiol group along with two benz'yl groups are removed. When'the reaction. is

substantially: complete the hydrogenvuptake'cease's, T he liydrbgeii bomb is allowed to cool, the catalyst filtered'oif and uie excess acetic acid distilled ofi. Th e residuef cont ing'thed'esired' product as a mixture Of acid and ester heiijbe dis'solved in analc ohol s' h as, ref r and and the residue mixed with a further solvent such as ethyl acetate, and then mixed with an alkali methyl carbonate or hydroxide solution. The desired product which is in the organic solvent layer is separated from the aqueous layer. After removal of the solvent the product can be purified by distillation under reduced pressure. Upon saponification of the esters, the acids can be obtained and on oxidation to the cyclic disulfide, they are usually solids which can be further purified by recrystallization from a suitable solvent such as n-butyl ether, cyclohexane, nitromethane, etc.

The following examples illustrate in greater particularity the preparation of the dithiol aliphatic acids and esters of the present invention.

EXAMPLE 1 Methyl 6,8-dithil0ctanoate A 1410 ml. stainless steel hydrogenation bomb was charged with 294.4 g. (1.0 mole) of methyl 8-benzylthio- 6-ketooctanoate, 186.3 g. (1.5 moles) alpha-toluene thiol, 0.125 mole of cobalt polysulfide acetic paste, and a small amount of acetic acid. The bomb was filled to 1600 lbs. with hydrogen and heated with shaking to 175 C. After about three hours the pressure had dropped to 800 lbs. The bomb was again filled with hydrogen and the temperature increased to 200 C. Hydrogen was added occasionally to keep the pressure between 1200 and 1600 lbs. After six hours total reaction time the hydrogen uptake was calculated to be 3.24 moles (theory 3 moles) and the reaction was stopped. The bomb was cooled overnight and the contents emptied out. The catalyst was filtered off and washed with methanol. The solvents were distilled off and the residue taken up in 300 ml. of methanol containing 5 ml. of sulfuric acid. The resulting solution was refluxed 90 minutes and the excess methanol distilled off. The residue was taken up in ethyl acetate and washed with water and sodium bicarbonate solution. The solvent was distilled off and the residue distilled under reduced pressure. The fractions were collected as follows:

N 0. B. P. 0.) Press. Wt. g. Nu"

4 EXAMPLE 3 Methyl 6,8-dithiol0ctanaate A 1410 ml. stainless steel hydrogenation bomb was charged with 1.61 moles of crude methyl 6,6,8-tris-benzyl thiooctanoate and 0.125 mole of cobalt polysulfide acetic acid paste. The bomb was filled to 1700 lbs. with hydrogen. The shaking was started and the bomb heated 150160 C. for two and one-half hours. The temperature was increased to 175 C. for two and one-half hours and to 180 C. for two hours. Hydrogen was added from time to time to keep the pressure between 800 and 1700 lbs. The total hydrogen uptake was calculated as 6.3 moles (theory 5.9). The bomb was cooled overnight,

the contents emptied out, the catalyst filtered off and washed with methanol. The filtrate was stripped of solvents under the reduced pressure of an aspirator. The residue was taken up in 300 ml. methanol containing 5 ml. sulfuric acid and refluxed two hours. The methanol was distilled off at the Water pump. The residue was taken up in ethyl acetate and washed with water and with g sodium bicarbonate solution. The residue was subjected to vacuum distillation. The fractions were collected as follows a Distilling residue.

Fraction No. 1 was largely alpha-toluene thiol which distilled 190 at 760 mm. Fractions 25, inclusive, were combined with the distilling residue and rehydrogenated using 0.125 mole of cobalt polysulfide acetic acid paste catalyst and 150 ml. acetic acid as solvent. The reduction was carried out for seven hours at 200 C. with hydrogen pressures of 10004600 lbs. A calculated 2.5 moles was taken up. The contents of the cooled bomb were washed up as above and this rehydrogenated mate- Fractions 2, 3, 4 and 5 represented the product methyl 6,8-dithiolactanoate.

EXAMPLE 2 Dithz'ooctanoic acid The crude ester, fractions 2, 3, 4 and 5 were combined and saponified by two hours with g. sodium hydroxide 1n 800 ml. water and left standing overnight. The aquerial again distilled.

No. B. P. Press. Wt., g.

6- 0. 3 66 Distilling residue.

Fractions 1-5, inclusive, from the above distillation were combined and fractionated through a 12-inch Stedrnan column. The fraction distilling from 152 to 158 at 3.8

mm. and weighing 69.3 g. was methyl 6,8-dithiooctanoate.

ous solution was acidified to pH 7 and extracted with ethyl V 40 g. of yellow crystals of 6,8-dithiooctanoic acid, melting point 58.559 C. The yield was 19.5% based on the methyl S-benzylthio-6-ketooctanoate.

- and acetic acids.

EXAMPLE 4 6,8-dithiooctan0ic acid The ester of Example 3 was saponified by standing 24 hours in a solution of m1. 5 N sodium hydroxide diluted to 500 ml. The aqueous suspension was extracted with ethyl acetate to remove a small amount of second phase. The aqueous solution was diluted to two liters with water and the pH adjusted to 7 with hydrochloric 5 ml. of 10% ferric chloride hexahydrate was added and oxygen bubbled through the rapidly stirred solution until the color changed from purple to light yellow. 500 ml. of ethyl acetate was added and the stirring solution acidified slowly with hydrochloric acid. The organic layer was separated and the aqueous layer extracted with 200 ml. ethyl acetate. The combined ethyl acetate solutions were dried over sodium lam- J in which R is a member of the group consisting of hydrogen lower alkyl radicals, R is a lower alkyl radical and n is a whole integer from 2 to 6, which comprises heating a compound having the formula:

in which R, R and n are as defined above with alphatoluene thiol and hydrogen in the presence of hydrogen ions and a sulfactive catalyst.

2. In a method of preparing compounds having the general formula:

in which R is a member of the group consisting of hydrogen and lower alkyl radicals, R is a lower alkyl radical and n is a whole integer from 2 to 6, the step which comprises heating a compound having the formula:

0 ll -omsonomo ompo-o1v (SCH in which R, R and n are as defined above with hydrogen in the presence of a sulfactive catalyst.

3. A method of preparing a lower alkyl ester of 6,8- dithioloctanoic acid which comprises heating a lower alkyl ester of 8-benzylthio-6-ketooctanoic acid with alpha-toluene thiol and hydrogen in the presence of hydrogen ions and a sulfactive catalyst.

4. A method of preparing methyl 6,8dithioloctanoate which comprises heating methyl 8-benzy1thio-6-ketooctanoate with alpha-toluene thiol and hydrogen in the presence of hydrogen ions and a sulfactive catalyst.

5. In a method of preparing methyl 6,8-dithioloctanoate the step which comprises heating methyl 6,6,8-trisbenzylthiooctanoate with hydrogen in the presence of a sulfactive catalyst. 

1. THE METHOD OF PREPARING COMPOUNDS HAVING THE GENERAL FORMULA: 